scholarly journals SARS-CoV-2 N Protein Targets TRIM25-Mediated RIG-I Activation to Suppress Innate Immunity

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1439
Author(s):  
Gianni Gori Savellini ◽  
Gabriele Anichini ◽  
Claudia Gandolfo ◽  
Maria Grazia Cusi
Keyword(s):  
Molecular Mechanisms ◽  
Rna Binding ◽  
Antagonistic Activity ◽  
Binding Activity ◽  
Host Immune System ◽  
The Novel ◽  
Protein Targets ◽  
N Protein ◽  
New Findings ◽  
Severe Clinical Picture

A weak production of INF-β along with an exacerbated release of pro-inflammatory cytokines have been reported during infection by the novel SARS-CoV-2 virus. SARS-CoV-2 encodes several proteins able to counteract the host immune system, which is believed to be one of the most important features contributing to the viral pathogenesis and development of a severe clinical picture. Previous reports have demonstrated that SARS-CoV-2 N protein, along with some non-structural and accessory proteins, efficiently suppresses INF-β production by interacting with RIG-I, an important pattern recognition receptor (PRR) involved in the recognition of pathogen-derived molecules. In the present study, we better characterized the mechanism by which the SARS-CoV-2 N counteracts INF-β secretion and affects RIG-I signaling pathways. In detail, when the N protein was ectopically expressed, we noted a marked decrease in TRIM25-mediated RIG-I activation. The capability of the N protein to bind to, and probably mask, TRIM25 could be the consequence of its antagonistic activity. Furthermore, this interaction occurred at the SPRY domain of TRIM25, harboring the RNA-binding activity necessary for TRIM25 self-activation. Here, we describe new findings regarding the interplay between SARS-CoV-2 and the IFN system, filling some gaps for a better understanding of the molecular mechanisms affecting the innate immune response in COVID-19.

scholarly journals Inactivation of SGS3 as Molecular Basis for RNA Silencing Suppression by TYLCV V2

2013 ◽  
Author(s):  
Yedidya Gafni ◽  
Vitaly Citovsky
Keyword(s):  
Rna Silencing ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Plant Immunity ◽  
Inhibitory Effect ◽  
Binding Activity ◽  
Plant Interactions ◽  
Subsequent Conversion ◽  
Tomato Pathogen ◽  
F Box Protein

The Israeli isolate of Tomato yellow leaf curl geminivirus(TYLCV-Is) is a major tomato pathogen, causing extensive crop losses in Israel and in the south-eastern U.S. Yet, little is known about the molecular mechanisms of its interaction with tomato cells. One of the most interesting aspects of such interaction is how the invading virus counteracts the RNA silencing response of the plant. In the former BARD project, we have shown that TYLCV-Is V2 protein is an RNA silencing suppressor, and that this suppression is carried out via the interaction of V2 with the SGS3 component of the plant RNA silencing machinery. This reported project was meant to use our data as a foundation to elucidate the molecular mechanism by which V2 affects the SGS3 activity. While this research is likely to have an important impact on our understanding of basic biology of virus-plant interactions and suppression of plant immunity, it also will have practical implications, helping to conceive novel strategies for crop resistance to TYLCV-Is. Our preliminary data in regard to V2 activities and our present knowledge of the SGS3 function suggest likely mechanisms for the inhibitory effect of V2 on SGS3. We have shown that V2 possess structural and functional hallmarks of an F-box protein, suggesting that it may target SGS3 for proteasomal degradation. SGS3 contains an RNA-binding domain and likely functions to protect the cleavage produces of the primary transcript for subsequent conversion to double-stranded forms; thus, V2 may simply block the RNA binding activity of SGS3. V2 may also employ a combination of these mechanisms. These and other possibilities were tested in this reported project. 

scholarly journals Novel Inhibitors of the Pseudomonas aeruginosa Virulence Factor LasB: a Potential Therapeutic Approach for the Attenuation of Virulence Mechanisms in Pseudomonal Infection

2011 ◽  
Vol 55 (6) ◽  
pp. 2670-2678 ◽  
Author(s):  
George R. A. Cathcart ◽  
Derek Quinn ◽  
Brett Greer ◽  
Pat Harriott ◽  
John F. Lynas ◽  
...  
Keyword(s):  
Virulence Factor ◽  
Bacterial Cell ◽  
Bacterial Biofilm ◽  
Host Immune System ◽  
The Novel ◽  
Tissue Destruction ◽  
Protein Targets ◽  
Proteolytic Action ◽  
Conventional Antibiotics

ABSTRACTPseudomonas elastase (LasB), a metalloprotease virulence factor, is known to play a pivotal role in pseudomonal infection. LasB is secreted at the site of infection, where it exerts a proteolytic action that spans from broad tissue destruction to subtle action on components of the host immune system. The former enhances invasiveness by liberating nutrients for continued growth, while the latter exerts an immunomodulatory effect, manipulating the normal immune response. In addition to the extracellular effects of secreted LasB, it also acts within the bacterial cell to trigger the intracellular pathway that initiates growth as a bacterial biofilm. The key role of LasB in pseudomonal virulence makes it a potential target for the development of an inhibitor as an antimicrobial agent. The concept of inhibition of virulence is a recently established antimicrobial strategy, and such agents have been termed “second-generation” antibiotics. This approach holds promise in that it seeks to attenuate virulence processes without bactericidal action and, hence, without selection pressure for the emergence of resistant strains. A potent inhibitor of LasB,N-mercaptoacetyl-Phe-Tyr-amide (Ki= 41 nM) has been developed, and its ability to block these virulence processes has been assessed. It has been demonstrated that thes compound can completely block the action of LasB on protein targets that are instrumental in biofilm formation and immunomodulation. The novel LasB inhibitor has also been employed in bacterial-cell-based assays, to reduce the growth of pseudomonal biofilms, and to eradicate biofilm completely when used in combination with conventional antibiotics.

scholarly journals A Comparative Analysis of Coronavirus Nucleocapsid (N) Proteins Reveals the SADS-CoV N Protein Antagonizes IFN-β Production by Inducing Ubiquitination of RIG-I

2021 ◽  
Vol 12 ◽  
Author(s):  
Yan Liu ◽  
Qi-Zhang Liang ◽  
Wan Lu ◽  
Yong-Le Yang ◽  
Ruiai Chen ◽  
...  
Keyword(s):  
Comparative Analysis ◽  
Rna Binding ◽  
Binding Activity ◽  
N Protein ◽  
Infectious Bronchitis ◽  
Diarrhea Virus ◽  
Multiple Strategies ◽  
Infected Cells ◽  
Global Threat ◽  
N Proteins

Coronaviruses (CoVs) are a known global threat, and most recently the ongoing COVID-19 pandemic has claimed more than 2 million human lives. Delays and interference with IFN responses are closely associated with the severity of disease caused by CoV infection. As the most abundant viral protein in infected cells just after the entry step, the CoV nucleocapsid (N) protein likely plays a key role in IFN interruption. We have conducted a comprehensive comparative analysis and report herein that the N proteins of representative human and animal CoVs from four different genera [swine acute diarrhea syndrome CoV (SADS-CoV), porcine epidemic diarrhea virus (PEDV), severe acute respiratory syndrome CoV (SARS-CoV), SARS-CoV-2, Middle East respiratory syndrome CoV (MERS-CoV), infectious bronchitis virus (IBV) and porcine deltacoronavirus (PDCoV)] suppress IFN responses by multiple strategies. In particular, we found that the N protein of SADS-CoV interacted with RIG-I independent of its RNA binding activity, mediating K27-, K48- and K63-linked ubiquitination of RIG-I and its subsequent proteasome-dependent degradation, thus inhibiting the host IFN response. These data provide insight into the interaction between CoVs and host, and offer new clues for the development of therapies against these important viruses.

scholarly journals Indian Ethnomedicinal Phytochemicals as Promising Inhibitors of RNA-Binding Domain of SARS-CoV-2 Nucleocapsid Phosphoprotein: An In Silico Study

2021 ◽  
Vol 8 ◽  
Author(s):  
Sankar Muthumanickam ◽  
Arumugam Kamaladevi ◽  
Pandi Boomi ◽  
Shanmugaraj Gowrishankar ◽  
Shunmugiah Karutha Pandian
Keyword(s):  
Medicinal Plants ◽  
Rna Binding ◽  
Research Work ◽  
Bioactive Molecules ◽  
Receptor Protein ◽  
Geranyl Acetate ◽  
Ocimum Sanctum ◽  
Host Immune System ◽  
Viral Receptor ◽  
N Protein

SARS-CoV-2, an etiological agent of COVID-19, has been the reason for the unexpected global pandemic, causing severe mortality and imposing devastative effects on public health. Despite extensive research work put forward by scientist around globe, so far, no suitable drug or vaccine (safe, affordable, and efficacious) has been identified to treat SARS-CoV-2. As an alternative way of improvising the COVID-19 treatment strategy, that is, strengthening of host immune system, a great deal of attention has been given to phytocompounds from medicinal herbs worldwide. In a similar fashion, the present study deliberately focuses on the phytochemicals of three Indian herbal medicinal plants viz., Mentha arvensis, Coriandrum sativum, and Ocimum sanctum for their efficacy to target well-recognized viral receptor protein through molecular docking and dynamic analyses. Nucleocapsid phosphoprotein (N) of SARS-CoV-2, being a pivotal player in replication, transcription, and viral genome assembly, has been recognized as one of the most attractive viral receptor protein targets for controlling the viral multiplication in the host. Out of 127 phytochemicals screened, nine (linarin, eudesmol, cadinene, geranyl acetate, alpha-thujene, germacrene A, kaempferol-3-O-glucuronide, kaempferide, and baicalin) were found to be phenomenal in terms of exhibiting high binding affinity toward the catalytic pocket of target N-protein. Further, the ADMET prediction analysis unveiled the non-tumorigenic, noncarcinogenic, nontoxic, non-mutagenic, and nonreproductive nature of the identified bioactive molecules. Furthermore, the data of molecular dynamic simulation validated the conformational and dynamic stability of the docked complexes. Concomitantly, the data of the present study validated the anti-COVID efficacy of the bioactives from selected medicinal plants of Indian origin.

scholarly journals Comprehensive Characterization of Androgen-Responsive circRNAs in Prostate Cancer

Life ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1096
Author(s):  
Zhe Kong ◽  
Yali Lu ◽  
Xuechao Wan ◽  
Jun Luo ◽  
Dujian Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
Rna Binding Proteins ◽  
Circular Rnas ◽  
Transcriptional Level ◽  
The Novel ◽  
Cancer Tissues ◽  
Posttranscriptional Level

The androgen receptor (AR) signaling pathway plays an important role in the initiation and progression of prostate cancer. Circular RNAs (circRNAs), the novel noncoding RNAs without 5′ to 3′ polarity or 3′ poly (A), play an important role in multiple diseases. However, the potential roles of androgen-responsive circRNAs in prostate cancer remain unclear. In this study, we identified 3237 androgen-responsive circRNAs and 1954 androgen-responsive mRNAs after dihydrotestosterone (DHT) stimulation using microarray. Among them, the expression of 1296 androgen-responsive circRNAs was consistent with that of their parent genes, and we thought AR might regulate the expression of these circRNAs at the transcriptional level. In addition, 1941 circRNAs expression was not consistent with their parent genes, and we speculated that AR may regulate the expression of those circRNAs at the posttranscriptional level through affecting alternative splicing. Analyzing the androgen-responsive circRNAs regulated at the posttranscriptional level, we identified two key RNA binding proteins (RBPs), WTAP and TNRC6, using the circInteractome database, which may play important role in the biogenesis of androgen-responsive circRNAs. Furthermore, we explored the potential biological functions and predicted the molecular mechanisms of two dysregulated circRNAs (circNFIA and circZNF561) in prostate cancer. In this study, we revealed that circNFIA was upregulated in prostate cancer tissues and plasma samples from patients with prostate cancer; circNFIA may play an oncogenic role in prostate cancer. In contrast, circZNF561 was downregulated and may act as a tumor suppressor in prostate cancer. Our results suggest that androgen-responsive circRNAs might regulate the progression of prostate cancer and could be novel diagnostic biomarkers.

scholarly journals Computational Guided Identification of Novel Potent Inhibitors of NTD-N-Protein of SARS-CoV-2

2020 ◽  
Author(s):  
Poonam Dhankhar ◽  
vikram dalal ◽  
Vishakha Singh ◽  
Shailly Tomar ◽  
pravindra kumar
Keyword(s):  
Rna Binding ◽  
Pharmacophore Model ◽  
Guanosine Monophosphate ◽  
Viral Rna ◽  
The Novel ◽  
N Protein ◽  
Legitimate Target ◽  
Zinc Database ◽  
Dynamics Simulations ◽  
Virus Replication Cycle

<p>The Coronavirus Disease 2019 (COVID-19), caused by the SARS-CoV-2 virus has raised severe health problems in china and across the world as well. CoVs encode the nucleocapsid protein (N-protein), an essential RNA-binding protein that performs different roles throughout the virus replication cycle and forms the ribonucleoprotein complex with viral RNA using the N-terminal domain (NTD) of N-protein. Recent studies have shown that NTD-N-protein is a legitimate target for the development of antiviral drugs against human CoVs. Owing to the importance of NTD, the present study focuses on targeting the NTD-N-protein from SARS-CoV-2 to identify the potential compounds. The pharmacophore model has been developed based on the guanosine monophosphate (GMP), a RNA substrate and further pharmacophore-based virtual screening was performed against ZINC database. The screened compounds were filtered by analysing the <i>in silico</i> ADMET properties and drug-like properties. The pharmacokinetically screened compounds (ZINC000257324845, ZINC000005169973, and ZINC000009913056) were further scrutinized through computational approaches including molecular docking and molecular dynamics simulations and revealed that these compounds exhibited good binding affinity as compared to GMP and provide stability to their respective complex with the NTD. Our findings could disrupt the binding of viral RNA to NTD, which may inhibit the essential functions of NTD. These findings may further provide an impetus to develop the novel and potential inhibitor against SARS-CoV-2.<br></p>

scholarly journals Structural dynamics of SARS-CoV-2 nucleocapsid protein induced by RNA binding

2021 ◽  
Author(s):  
Helder Veras Ribeiro Filho ◽  
Gabriel Ernesto Jara ◽  
Fernanda Aparecida Heleno Batista ◽  
Gabriel Ravanhani Schleder ◽  
Celisa Caldana Tonoli ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Rna Binding ◽  
Structural Data ◽  
Binding Activity ◽  
Full Length ◽  
N Protein ◽  
Intrinsically Disordered ◽  
Virus Life Cycle ◽  
Biophysical Techniques ◽  
Dynamics Simulations

AbstractThe nucleocapsid (N) protein of the SARS-CoV-2 virus, the causal agent of COVID-19, is a multifunction phosphoprotein that plays critical roles in the virus life cycle, including transcription and packaging of the viral RNA. To play such diverse roles, the N protein has two structured RNA-binding modules, the N- (NTD) and C-terminal (CTD) domains, which are connected by an intrinsically disordered region. Despite the wealth of structural data available for the isolated NTD and CTD, how these domains are arranged in the full-length protein and how the oligomerization of N influences its RNA-binding activity remains largely unclear. Herein, using experimental data from electron microscopy and biochemical/biophysical techniques combined with molecular modeling and molecular dynamics simulations, we show that, in the absence of RNA, the N protein forms structurally dynamic dimers with the NTD and CTD arranged in extended conformations. In the presence of RNA, however, the N protein assumes a more compact conformation where the NTD and CTD are packed together. We also provide an octameric model for the full-length N bound to RNA that is consistent with electron microscopy images of the N protein in the presence of RNA. Together, our results shed new light on the dynamics and higher-order oligomeric structure of this versatile protein.

scholarly journals ELAV proteins bind and stabilize C/EBP mRNA in the induction of long-term memory in Aplysia

2020 ◽  
Author(s):  
Anastasios A. Mirisis ◽  
Ashley M. Kopec ◽  
Thomas J. Carew
Keyword(s):  
Gene Expression ◽  
Molecular Mechanisms ◽  
Rna Binding ◽  
De Novo ◽  
Rna Binding Proteins ◽  
Early Gene ◽  
Long Term Memory ◽  
Term Memory ◽  
New Findings

AbstractLong-term memory (LTM) formation is a critical survival process by which an animal retains information about prior experiences in order to guide future behavior. In the experimentally advantageous marine mollusk Aplysia, LTM for sensitization can be induced by the presentation of two aversive shocks to the animal’s tail. Each of these training trials recruits distinct growth factor signaling systems that promote LTM formation. Specifically, whereas intact TrkB signaling during Trial 1 promotes an initial and transient increase of the immediate early gene apc/ebp mRNA, a prolonged increase in apc/ebp gene expression required for LTM formation requires the addition of TGFβ signaling during Trial 2. Here we explored the molecular mechanisms by which Trial 2 achieves the essential prolonged gene expression of apc/ebp. We find that this prolonged gene expression is not dependent on de novo transcription, but that apc/ebp mRNA synthesized by Trial 1 is post-transcriptionally stabilized by interacting with the RNA-binding protein ApELAV. This interaction is promoted by p38 MAPK activation initiated by TGFβ. We further demonstrate that blocking the interaction of ApELAV with its target mRNA during Trial 2 blocks both the prolonged increase in apc/ebp gene expression and the behavioral induction of LTM. Collectively, our findings elucidate both when and how ELAV proteins are recruited for the stabilization of mRNA in LTM formation.Significance StatementIn the present paper we significantly extend the general field of molecular processing in LTM by describing a novel form of pre-translational processing required for LTM which relies on the stabilization of a newly synthesized mRNA by a unique class of RNA binding proteins (ELAVs). In the broad field of molecular mechanisms of transcription-dependent LTM, there are now compelling data showing that important processing can occur after transcription of a gene, but before translation of the message into protein. Although the potential importance of ELAV proteins in LTM formation has previously been reported, to date there has been no mechanistic insight into the specific actions of ELAV proteins in stabilization of mRNAs known to be critical for LTM. Our new findings thus complement and extend this literature by demonstrating when and how this post-transcriptional gene regulation is mediated in the induction of LTM.

scholarly journals Computational Guided Identification of Novel Potent Inhibitors of NTD-N-Protein of SARS-CoV-2

2020 ◽  
Author(s):  
Poonam Dhankhar ◽  
vikram dalal ◽  
Vishakha Singh ◽  
Shailly Tomar ◽  
pravindra kumar
Keyword(s):  
Rna Binding ◽  
Pharmacophore Model ◽  
Guanosine Monophosphate ◽  
Viral Rna ◽  
The Novel ◽  
N Protein ◽  
Legitimate Target ◽  
Zinc Database ◽  
Dynamics Simulations ◽  
Virus Replication Cycle

<p>The Coronavirus Disease 2019 (COVID-19), caused by the SARS-CoV-2 virus has raised severe health problems in china and across the world as well. CoVs encode the nucleocapsid protein (N-protein), an essential RNA-binding protein that performs different roles throughout the virus replication cycle and forms the ribonucleoprotein complex with viral RNA using the N-terminal domain (NTD) of N-protein. Recent studies have shown that NTD-N-protein is a legitimate target for the development of antiviral drugs against human CoVs. Owing to the importance of NTD, the present study focuses on targeting the NTD-N-protein from SARS-CoV-2 to identify the potential compounds. The pharmacophore model has been developed based on the guanosine monophosphate (GMP), a RNA substrate and further pharmacophore-based virtual screening was performed against ZINC database. The screened compounds were filtered by analysing the <i>in silico</i> ADMET properties and drug-like properties. The pharmacokinetically screened compounds (ZINC000257324845, ZINC000005169973, and ZINC000009913056) were further scrutinized through computational approaches including molecular docking and molecular dynamics simulations and revealed that these compounds exhibited good binding affinity as compared to GMP and provide stability to their respective complex with the NTD. Our findings could disrupt the binding of viral RNA to NTD, which may inhibit the essential functions of NTD. These findings may further provide an impetus to develop the novel and potential inhibitor against SARS-CoV-2.<br></p>

Concussion in sports in children and adolescents – to play or not to play?

2017 ◽  
Vol 65 (3) ◽  
Keyword(s):  
Gender Differences ◽  
Children And Adolescents ◽  
Return To Sport ◽  
Consensus Conference ◽  
Return To School ◽  
The Novel ◽  
International Consensus ◽  
Persistent Symptoms ◽  
New Findings

A lot has been published on the topic concussion in sports during the last years, conscience was sharpened, much was structured and defined more precisely, help tools were developed and rules changed. This article summarizes the fifth edition of the recently published guidelines of the “International Consensus Conference on Concussion in Sport”. In addition, new findings regarding gender differences and recovery will be presented, as well as the modified “return-to-sport” and the novel “return-to-school” protocols. Despite increased knowledge many questions remain such as the therapy of persistent symptoms or long-term sequelae of recurrent concussions.

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